According to the American Association for Cancer Research (“AACR”) Task Force on the Treatment and Prevention of Intraepithelial Neoplasia (O'Shaughnessy et al. (2002), “intraepithelial neoplasia (“IEN”) is a non-invasive lesion that has genetic abnormalities, loss of cellular control functions, and some phenotypic characteristics of invasive cancer and that predicts for a substantial likelihood of developing invasive cancer.” IEN is believed to occur in most epithelial tissue as moderate to severe dysplasia, on the causal pathway leading from normal tissue to cancer.
The AACR Task Force indicates that “[a]lthough several effective endoscopic and surgical treatments for IEN have become standard medical practice, these interventions can confer morbidity and do not treat the entire epithelial field at risk.” The Task Force suggests that the “incidence of many epithelial cancers is continuing to rise, the number of individuals at risk is increasing with the aging population . . . ” Hence, the Task Force concludes that there is “an urgent need to rapidly develop new treatment and prevention agents for IEN.” The Task Force recommends such treatment because of the close association between dysplasia and invasive cancer and because a convincing reduction in IEN burden provides patient benefit by reducing cancer risk and/or by decreasing the need for invasive intervention.
O'Shaughnessy et al. (2002) describes the stages of progression from normal tissue to cancer as including the stages of: initiation of dysplasia, development of mild dysplasia, development of moderate dysplasia, development of severe dysplasia, development of carcinoma in situ (“CIS”), and finally development of cancer (invasive neoplasia).
Thus, for example, for colon cancer, it takes about 5-20 years to progress from normal tissue to the adenoma stage (pre-mild dysplasia), then another 5-15 years to progress from the adenomatous IEN stage, to cancer. For head and neck tumors, it takes about 4-10 years of tobacco use to develop dysplastic oral leukoplakia, and another 6 to 8 years to progress to cancer. For the esophageal tumors, tissues exhibiting the characteristics of Barrett's syndrome progress to severe dysplasia in about 9-13 years, and to cancer in another 3-4 years. For cervical tumors, tissues exhibiting the characteristics of cervical intraepithelial neoplasia (“CIN”) are at the initiation of dysplasia stage. The CIN-exhibiting tissues take about 9-13 years to progress to CIN grade 3 or CIS, and another 10-20 years to become cancerous. For lung cancers in general, it takes about 5-20 years for normal tissues to become cancerous. For smokers, lung cancer can be developed over a period of 20-40 cigarette pack-years. For non-melanoma skin cancer, normal tissues progress to the IEN stage in about 30-40 years, and then to cancer in about another 10 years. For breast tumors, tissues exhibiting characteristics of atypical hyperplasia progress to ductal CIS (“DCIS”) in about 14-18 years, and from DCIS to cancer in about another 6-10 years. For prostate tumors, it takes about 20 years to progress from normal to prostatic intraepithelial neoplasia (“PIN”), then another 10 years or more to progress to latent cancer stage, and a further 3-15 years to progress to invasive cancer stage. For bladder tumors, it takes about 20 years to progress to transitional cell carcinoma in situ (“TIS”), and less than another 5 years to progress from this IEN stage to invasive cancer.
Colon cancer and rectal cancer (collectively, “colorectal cancer” or “CRC”) is known to be the third most common cause of cancer-related death in the United States, after lung and prostate cancer in men, and lung and breast cancer in women. Colorectal carcinogenesis is believed to be a multistage process. The first clinically detectable evidence of IEN consists of subtle alterations in the regular pattern of the intestinal crypts known as aberrant crypt foci (“ACF”). “ACF may show loss of wild-type adenomatous polyposis coli (“APC”) protein, as well as mutations of K-ras.”
Head and neck squamous cell carcinoma (“HNSCC”) comprises oral cavity, oral pharynx and laryngeal cancers. The primary risk factors for HNSCC include smoking tobacco and alcohol consumption. The overall survival rate for these cancers (˜55%) is not significantly improved over the last three decades. It is believed that although many different changes contribute to epithelial carcinogenesis, histologically, defined IEN lesions are still considered to be a better predictor of cancer risk than any individual genetic lesion. The oral IEN lesions (“OPLs”) are white and/or red mucosal patches in the oral cavity or oropharynx that occur in about 1-10% of the adult population in the Western world. “Histological patterns of OPLs vary from hyperkeratosis with hyperplasia to severe dysplasia or CIS.”
Barrett's esophagus is believed to be the “primary IEN precursor to esophageal adenocarcinoma.” The AACR Task Force in O'Shaughnessy et al. (2002) indicates that esophageal cancer is associated with the third lowest 5-year survival rate among all cancers (behind pancreas and liver). Barrett's esophagus is “a condition in which normal esophageal squamous epithelium is replaced by a metaplastic columnar lining resembling intestinal epithelium,” and is believed to be “strongly associated with chronic GERD (gastroesophageal reflux disease).”
Cervical cancer is believed to be the third most common cancer in women worldwide. The precursor lesion to invasive cervical cancer, CIN, is also known as SIL (squamous intraepithelial lesion) of the cervix. “It arises at the junction between the primary columnar epithelium of the endocervix and the squamous epithelium of the ectocervix, a site of continuous metaplastic change.” SILs are classified as low grade (LGSIL) and high grade (HGSIL). LGSILs include CIN 1 lesions; HGSILs include CIN 2 and 3 and CIS, according to the Bethesda System. (The Bethesda System for reporting cervical/vaginal cytological diagnoses (1989)) and Kurman, R. J. et al. (1994).
Bronchial intraepithelial neoplasia is the precursor to lung cancer. In the United States, lung cancer is the most common cause of cancer death in both men and women. It is believed that more patients die from lung cancer than from breast, colon, and prostate cancers combined. Like other epithelial malignancies, lung cancers are preceded by a series of precursor lesions. For squamous cell carcinoma (“SCC”), invasive lung cancer develops from first mild, then moderate and severe atypia, then CIS, and then invasive cancer over an average of 10 years. Not much is known about the development of other lung tumor types, but atypical adenomatous hyperplasia of the lung (“AAH”) is considered to be the preinvasive lesion of adenocarcinoma.
Non-melanoma skin cancer is the most common type of malignancy. The incidence of skin cancer continues to grow, but mortality attributable to this disease is relatively low. Yet, morbidity can be dramatic because tumors are often disfiguring and located in facial areas, requiring excision of lesions in cosmetically sensitive areas. Keratinocytic non-melanoma skin cancers originate in the epidermis and consist of basal cell carcinoma (“BCC”) and squamous cell carcinoma (“SCC”). About 80% of such tumors are BCCs, which appear to originate from basal cells of the epidermis and occasionally those of the infundibular and outer root sheath of the hair follicles. These are slow-growing tumors that are locally invasive but rarely metastasize. SCCs appear to originate in the keratinizing cells of the epidermis. SCCs are generally more aggressive than BCCs and have a much higher potential for metastasis. IEN precursor to
SCC appears as a proliferation of transformed, neoplastic keratinocytes confined to the epidermis and is characterized by thickened, cornified, scaly lesions that develop on the surface of the skin because of improper maturation of keratinocytes.
Breast cancer is believed to be the most common cancer in women excluding BCCs and SCCs of skin and the second most common cause of cancer deaths in women. Breast IEN, which spans the continuum from simple hyperplasia without atypia to CIS, is a recognized risk factor for invasive breast cancer. The predominant phenotype in breast IEN is reportedly a progressive increase in the proportion of cells expressing estrogen receptor (“ER”). An increase in growth factors, growth factor expression, receptor tyrosine kinase activity and proliferation as well as diminished apoptosis is observed in early breast IEN. Women with newly diagnosed advanced TEN, including atypical hyperplasia, lobular CIS (“LCIS”), ductal CIS (“DCIS”), are often offered treatment with 5 years of tamoxifen to reduce the risk of invasive breast cancer.
Prostate cancer is believed to be the most common cancer in males in the United States, accounting for about 29% (180,400) of all new cancers and 11% (31,900) of cancer deaths in males in 2001. Prostate intraepithelial neoplasia (“PIN”) is believed to be a morphological and genetic precursor to prostate cancer. PIN lesions are found to be characterized by collections of proliferative prostatic epithelial cells confined within prostatic ducts that exhibit many morphological features of prostate cancer cells. Such features include architectural disorganization, enlarged cell nuclei and nucleoli. PIN lesions are currently classified into two grades, low-grade PIN (formerly PIN 1) and high-grade PIN (HGPIN, formerly PIN 2 and PIN 3). Current use of the term PIN generally refers only to HGPIN. Evidence that HGPIN is a precursor of prostatic adenocarcinoma includes multifocality of both lesions and the presence of carcinoma in foci of PIN. PIN is usually localized in the peripheral zone of the prostate, where 70% of prostatic carcinomas occur. Both PIN and carcinoma exhibit enhanced proliferative activity (about 3 fold that of benign tissue), cytokeratin immunoreactivity, lectin binding, and loss of blood group antigen. PIN lesions are asymptomatic and cannot be easily diagnosed or detected except through examination of prostate tissue histologically. Available evidence supports the conclusion that presence of PIN on prostate biopsy predicts for an increased risk for prostate cancer and that some PIN give rise to prostate cancers.
Bladder cancer is believed to be the fourth most common cancer in males in the United States, accounting for 6% (39,200) of new cancer cases and 3% (8,300) of cancer-related deaths in 2001. In United States females, the incidence is lower with 2% (15,100) of new cases and less than 2% (4,100) of cancer deaths. Of these cancers that are confirmed histologically, the majority is transitional cell carcinoma (“TCC”). Invasive TCC are thought to arise from one of two IEN precursor lesions, papillary TCC and transitional cell carcinoma in situ (“TIS”). Papillary TCC is the most common bladder tumor, characterized by papillae protruding into the bladder lumen and composed of several layers of urothelial cells. The urothelial cells exhibit a spectrum of cytological atypia and proliferative activity, with grade 1 lesions showing slight cytological atypia and some mitoses, grade 2 showing moderate cytological atypia and some mitoses, and grade 3 lesions showing marked nuclear atypia and frequent mitoses. Lower grade flat lesions in the bladder, often termed mild dysplasia and moderate dysplasia are also recognized. TCC and TIS can be distinguished from invasive carcinoma in that the latter is characterized by progressive penetration of cancer cells through the lamina propria of the bladder urothelium into the underlying musculature. Superficial bladder cancers, i.e., papillary TCC and TIS, and invasive bladder cancers often present with symptoms of hematuria or discomfort.
Vulval intraepithelial neoplasia (“VIN”) is defined as the pre-invasive phase of carcinoma of the vulva. It affects 20 to 30 per 100,000 women, with women under 41 constituting 40% of the cases. VIN presents as pruritus vulvae or abnormal skin lesion of the vulva. Management options include local excision and careful monitoring or steroidal treatment. Approximately 6% of the lesions become malignant. It is further believed that if VIN is diagnosed, then there is a greater than 10% risk of neoplasia elsewhere, generally in the cervix.
Pancreatic intraepithelial neoplasia (“PanIN”) has been classified into three grades. PanIN 2 and PanIN 3 are believed to be precursors to invasive pancreatic carcinoma. Pancreatic neoplasms can be classified phenotypically based on their cellular lineages, such as ductal, acinar and endocrine phenotypes. Most pancreatic neoplasms are of the ductal type and can be classified as ductal adenocarcinomas. Less common tumors with a ductal phenotype include variants of ductal adenocarcinoma, intraductal papillary mucinous neoplasm including colloid carcinoma, mucinous cystic neoplasm, medullary carcinoma, and other rare tumors. Ductal adenocarcinomas are believed to have developed from ductal proliferative lesions arising in the pancreatic duct system, as described in Kloppel, G. and Luttges, J. (2004) and Takaori, K. et al. (2004).
Other intraepithelial neoplasias that are precursors to invasive cancers have been reported. For example, anal intraepithelial neoplasia (“AIN”) presenting as bowenoid papulosis and perianal Bowen disease is believed to be a precursor lesion for invasive squamous cell carcinoma, as described in Wacker, J. and Hartschuh, W. (2004). Testicular intraepithelial neoplasia (“TIN”) is believed to be a precursor of testicular germ cell tumors, as described in Dieckmann, K. P. and Pichlmeier, U. (2004). Penile intraepithelial neoplasia (“PenileIN”) may be a precursor to high-grade PenileIN and anogenital carcinoma, as described in Aynaud, O. and Bergeron, C. (2004). Conjunctival-corneal intraepithelial neoplasia (“CCIN”) is described in Dudney, B. W. and Malecha, M. A. (2004).
Jordan et al. in U.S. Pat. No. 5,008,294 claims the use of certain catecholic butanes for “inhibiting the growth of a tumor which comprises topically administering to the situs of the tumor of a mammal in need of said treatment an effective amount of a composition comprising at least 1 catecholic butanes” of a specified formula. Jordan et al. further claims treatment for tumors of the skin, keratosis of the skin, and actinic keratosis.
McDonald, R. W. wt al. (2001) synthesized five analogues of NDGA with different lengths of carbon bridge between the two catechol moieties and five analogues of NDGA containing only one hydroxyl group on each aromatic ring.
Huang et al., in U.S. Pat. No. 6,365,787 and U.S. Pat. No. 5,663,209, claim certain novel NDGA derivatives that were isolated from Larrea tridentate and use thereof for the suppression of Tat transactivation of a lentivirus in a cell. Hwu, J. R. et al. (1998) described the synthesis of mono-, di-, tri-, and tetra-O-methylated NDGA and isolation of such in pure forms.
Huang et al., in U.S. Pat. No. 6,214,874, further claim, among other things, methods for treating HPV-induced tumor comprising application of at least one NDGA derivative of a specified formula. Additionally, in U.S. Pat. No. 6,417,234, Huang et al. describes, among other things, a method of treating tumors using at least one NDGA derivative of a specified formula. In U.S. Pat. No. 6,608,108, Huang et al. claim, among other things, methods of inhibiting survivin production in a eukaryotic cell cycle and methods of stimulating apoptosis in a cell expressing CDC-2 and survivin.
There is an urgent medical need to develop compositions, kits and methods for treatment of intraepithelial neoplasia of all epithelial cell types so as to reduce the morbidity and mortality of cancer.